The management of asthma has changed significantly over the past decade, reflecting the recognition of a coincident chronic pulmonary inflammation. Asthma appears to be pluricausal in origin, involving several genes and exacerbating factors, such as air pollution, allergies, cold sensitivity, viral infection, and tobacco/chemical exposure. See, for example, Daniels, S. E. et al., Nature, 383(6597):247-250, 1996; McBride, D. E. et al., Am. J. Resp. Crit. Care Med., 149(5):1192-1197, 1988; and O'Byrne, P. M., J. Aller. Clin. Immunol., 81(1):119-127, 1988. The wide variability among patients, both in terms of etiology and presentation of symptoms, is anchored by three common characteristic features: reversible variable airflow limitations, specific airway histopathologies, and airway hyperresponsiveness (AHR, i.e., the development of bronchoconstriction in response to nonspecific stimuli). Additional indicators of asthma include mucus overproduction, increased expression of IL-4 and IL-5, increased serum IgE levels, and often (70-90% of reported cases) the increased presence of eosinophils in the airway mucosa and lumen. The pathophysiological manifestations of asthma correlate with this eosinophilic airway infiltration. Indeed, eosinophil influx has been associated with the development of lung dysfunction even in mild cases of asthma. The concurrent appearance of pulmonary pathologies and eosinophil recruitment to the lung suggests that a causative relationship exists.
Eosinophil effector functions are mediated by several concurrent mechanisms including the secretion of small molecule mediators of inflammation (e.g., PAF, leukotrienes, proinflammatory cytokines such as interleukins 4, 5, and 8), antigen presentation and the release of granule components (i.e., degranulation). These mechanisms contribute to several inflammatory pathways. For example, secretion of inflammatory signals by eosinophils results in vasodilation and tissue edema and the recruitment/activation of other effector cells. Moreover, the ability of eosinophils to act as antigen presentation cells suggests that their recruitment to the lung during allergic inflammation may result in presentation of aeroallergens to resident T cells and thus initiate and/or amplify pulmonary immune responses.
A growing literature exists indicating that the release of eosinophil secondary granule proteins (ESGPs) is a critical effector function. ESGPs effector functions include not only cytotoxic activities leading to airway damage and lung dysfunction (e.g., AHR), but also agonist activities on several other cell types. Gleich, G. J. and C. Adolphson, Agents Actions Suppl., 43:223-230, 1993. For example, in vitro studies of lung fibroblasts have shown that ESGPs are capable of modulating gene expression from these cells. Rochester, C. L. et al., J. Immunol., 156(11):4449-4456, 1996. Furthermore, ESGPs also modulate the activation state and genes expressed by other leukocyte effector cells including neutrophils and mast cells. Agonist activities also extend to autocrine effects on eosinophils leading to the expression of inflammatory mediators and eosinophil degranulation. Patella, V. et al., J. Immunol., 157(3):1219-1225, 1996. These studies suggest that the interplay of ESGP effector functions have pleiotropic effects on the lung resulting in both tissue destruction and the modulation of inflammatory responses associated with allergic pulmonary inflammation. The four prominent murine secondary granule constituents include eosinophil peroxidase (EPO), major basic protein (MBP), and eosinophil associated ribonucleases (EAR-1 and EAR-2). EPO, MBP, eosinophil cationic protein (ECP), and eosinophil-derived neurotoxin (EDN) are the prominent secondary granule constituents in humans.